The aging brain exhibits an increased inflammatory potential which in turn elicits behavioral changes e.g., social withdrawal. Social isolation is a risk factor for additional health complications, and interventions which can mitigate these negative facets of aging can improve longevity and quality of life in old age. The circadian system critically regulates neuroimmune function and behavior, but circadian rhythms also degrade with age, resulting in lower amplitude oscillations in activity and hormone secretion. Time-restricted feeding (TRF), in which food availability is limited to a specific time-of-day, is a simple dietary intervention which provides timing cues to the circadian system - protecting against metabolic disease and reducing systemic inflammation. We thus tested the hypothesis that TRF could serve as an intervention to bolster circadian rhythms in aged mice and have beneficial effects upon age-associated neuroinflammation and behavior. Here, we demonstrate that 6 weeks of TRF in aged (18 months old) mice ameliorates age-associated social withdrawal and drives distinct molecular and cellular changes within the brain. TRF attenuates age-associated increases in inflammatory gene expression in the hippocampus and prefrontal cortex, and re-establishes circadian phase-appropriate expression of autophagy-related genes in the hippocampus. In addition, TRF promotes a diurnal rhythm in microglial branching complexity in the hippocampus, recapitulating the pattern observed in young adults (3 months old). TRF also reduced blood glucose levels in aged males, but not in aged females, suggesting sex-specific effects on metabolic parameters with age. These results highlight the efficacy of TRF as a therapeutic approach to alleviate age-associated neuroinflammation and social withdrawal.
